The endogenous opioid system comprises of three principal opioid receptor types in the central nervous system and in the periphery designated as μ (Mu), κ (Kappa) and δ (Delta). The pharmacological response is elicited by binding of a multitude of endogenous opioid ligands to these receptors, the principal ligands being—the enkephalins, endorphins, and dynorphins. The exogenous opioids/opiates exert their activity by mimicking and/or antagonizing the activity of the endogenous opioid ligands at these receptors. Since the anatomical location, distribution and function of the opioid receptors is wide and varied (Neuropharmacology, 21, 487-497; Med. Res. Rev., 11, 357-374), the pharmacological effects elicited by their agonism and antagonism are diverse as well.
The μ receptors which bind morphine and its derivatives are responsible for analgesia, respiratory and gastrointestinal functions, sedation, neuroendocrine functions and mediate opiate dependence. The δ receptors are abundant in the CNS and mediate analgesia, feeding and various hormonal functions. The κ receptors have a wide distribution in the CNS and the PNS; for example, centrally, these receptors are expressed in caudate—putamen, nucleus accumbens, amygdale, neural lobe of the pituitary gland, etc., and peripherally, they are expressed in the sensory neuron DRG, stomach, duodenum, jejunum, oleum, proximal and distal colon (Acta Neurobiol Exp., 71: 129-138). The κ receptors are responsible for functions including analgesia, gastrointestinal functions like food intake, gut motility; water balance, thermoregulation and various neuroendocrine functions. (J. Pharmacol. Exp. Ther. 234, 463-469; Peptides 4, 797-800; Goodman and Gilman's The Pharmacological Basis of Therapeutics (11th Edition) Chapter 21, Pp 547-590).
Pharmacologic studies with receptor selective ligands have shown that analgesia can be produced by selective activation of each of the three types of opioid receptors. Most clinically used opioid analgesics such as morphine and codeine act as μ receptor agonists. These opioids have well-known, undesirable and potentially dangerous dependence forming side effects associated with their CNS activity. κ opioid receptors, on the other hand, have attracted special attention due to their ability to act peripherally and produce analgesia without causing dependence and respiratory depression that is typically associated with μ receptor activation by morphine (Pharmaceutica Acta Helvetiae, 74, 2-3, Pp 337-344).
The opioid receptors are members of the superfamily of G-protein-coupled receptors (GPCRs). Agonist binding to the κ receptor activates the intracellularly associated G protein, which decreases Ca2+ channel conductance or inhibits adenylyl cyclase (AC). In addition to analgesia, potential applications of κ selective agonists include the areas of diuresis (Pharmacology Biochemistry and Behavior, 65, 1, Pp 53-59), eating disorders, motion sickness, and neuroprotection (Peptides 29, 12, Pp 2292-2375). Therefore, the κ receptors represent important therapeutic targets. Ligands selective for the κ receptors can serve as important pharmacologic tools. For example, such compounds can be used in competition assays to determine the relative specificity and selectivity of other compounds for the κ receptor, as well as for μ and δ receptors.
A large number of classes of compounds which act as KOR agonists have been described in the art including the following illustrative classes of compounds.
U.S. Pat. No. 7,112,598 describes KOR agonist comprising 2-phenylbenzothiazoline derivatives.
U.S. Pat. No. 5,681,830 describes diarylmethyl piperazine compounds having utility as exogenous receptor combinant species for binding with opioid receptors such as kappa receptors.
EP663401 describes morphinan derivatives as selective KOR agonists and their application as an analgesic, diuretic, antitussive and brain cell protective agent.
κ opioid receptor (commonly known as KOR) modulation has also been reported to be useful in the treatment of arthritis (Life Sciences, 57, 4, Pp 371-378), hypertension, pain, particularly pain which is inflammatory in origin and post-operative pain, (European Journal of Pharmacology, 429, 1-3, Pp 79-91) inflammation, migraine, inflammatory disorders of the gastrointestinal tract, psoriasis, and irritable bowel syndrome (IBS), Parkinsonism, (European Journal of Pharmacology, 396, 2-3, Pp 101-107, Molecular Brain Research, 44, 1, Pp 12-20) and stroke.
Accordingly, it is an object of the application to provide compounds as KOR agonists.
SUMMARY
The present application relates to compounds of formula (I),
stereoisomers thereof or pharmaceutically acceptable salts thereof;wherein,
R1 represents hydrogen, alkyl, haloalkyl or —(CH2)m-cycloalkyl;
R2 represents (1) cycloalkyl, (2) an group selected from heterocyclyl, heteroaryl or aryl, wherein such group is optionally substituted with 1 to 3 substituents selected independently from cyano, hydroxyl, alkyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkoxy, —COORa, —CONReRf, —O—(CH2)n—R7 or R11;
R3 is an optionally substituted group selected from

Optional substituent on R3, in each occurrence, independently selected from halogen, alkyl or haloalkyl;
R4 is selected from hydrogen, hydroxyl, halogen, alkyl, alkoxy, or haloalkyl;
R5 and R6, each are independently selected from hydrogen or alkyl;
R7 is selected from cyano, tetrazolyl, —COORa, —CONReRf or

R8, in each occurrence, is independently selected from hydrogen, halogen, alkyl or —(CH2)q—R9;
R9 is —COORa or

R10 is selected from hydrogen, cyano, —COORc, —CONReRf or tetrazolyl;
R11 is selected from (1) (C3-C6)cycloalkyl, benzyl,
or (2) 5-6 membered heteroaryl optionally substituted with 1 to 2 substituents selected independently from alkyl, haloalkyl, haloalkoxy or —(CH2)m—(C3-C6)cycloalkyl;
Ra and Rc, in each occurrence, independently selected from hydrogen, alkyl, heterocyclyl or heteroaryl;
Rb, in each occurrence, independently selected from hydrogen, alkyl or alkoxy;
Re, in each occurrence, independently selected from hydrogen, alkyl, haloalkyl or —S(O)2-alkyl;
Rf, in each occurrence, independently selected from hydrogen or alkyl;
m is selected from 0, 1, 2, 3 or 4;
n and q, each independently selected from 1 or 2;
provided that when R2 is phenyl optionally substituted with alkyl, alkoxy or halogen, R1 is alkyl and one of R5 and R6 represents hydrogen, then R3 does not represent the following rings
wherein Ri, in each occurrence, represents hydrogen or alkyl.
In another embodiment, the application is directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula (I), stereoisomer thereof or pharmaceutically acceptable salt thereof.
In one embodiment, the application is directed to novel compounds of formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof as κ opioid receptor (KOR) agonists.
In other embodiment, the application is directed to a method for binding opioid receptor, in a patient in need thereof, comprising administering to said patient a composition comprising an effective amount of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
In another embodiment, the application is directed to a method of treating or preventing gastrointestinal dysfunction, in a patient in need thereof, comprising administering to said patient a composition comprising an effective amount of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
In another embodiment, the application is directed to a method of treating or preventing pain, to a patient in need thereof, comprising administering to said patient a composition comprising an effective amount of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
In another embodiment, the application is directed to a method of administering KOR agonists in a subject, which comprises administering to the subject a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.